There is increasing recognition that intercellular communication is essential for cellular homeostasis, proliferation and differentiation. Such communication is believed to be facilitated by gap junctions. These structures are thought to be a route for coupling cells and permitting “cross-talk.” (See generally, Sperelakis N., eds., Cell Interactions and Gap Junctions, CRC Press, Inc. (1989)). The cross-talk between gap junctions is referred to as “gap junctional intercellular communication” (GJIC).
Generally, gap junctions are specialized regions of the cell membrane that contain clusters of hundreds to thousands of densely packed channels that directly connect the cytoplasm of two adjacent cells. The gap junction channels are composed of two hemichannels, or connexons, provided by each of two neighboring cells. Each connexon, in turn, is made up of six proteins called connexins.
In the heart, conduction of electrical impulses takes place through gap junctions. Abnormal GJIC has been linked to a variety of disease states, including heart disease. For example, it has been shown that mice heterozygous for the Cx43 gene, which codes for a specific ventricular connexin, develop spontaneous ventricular arrhythmias and suffer from sudden cardiac death. (Guerrero et al., J. Clin. Invest., 99, 1991-1998 (1997)). Reduced expression of Cx43 in heterozygous mice is directly linked to an increased incidence of ventricular arrhythmias during ischemia. (Lerner et al., Circulation, 101, 547-552 (2000)). Several other studies have shown reduced expression or altered distribution of Cx43 in chronically ischemic, hibernating, or hypertrophied hearts. (Kaprelian et al., Circulation, 97, 651-660 (1998); Peters et al., Circulation, 88, 864-875 (1993); Saffitz et al., Cardiovasc. Res., 42, 309-317 (1999)).
Several peptides that influence GJIC have been identified, including antiarrhythmic peptides AAP (Aonuma et al., Chem. Pharm. Bull. (Tokyo), 28, 3332-3339 (1980)), AAP10 (Dhein et al., Naunyn Schmiedebergs Arch Pharmacol., 350, 174-184 (1994); Muller et al., Eur. J. Pharmacol., 327, 65-72 (1997)), and HP5 (disclosed in U.S. Pat. No. 4,775,743). However, these peptides exhibit undesirable characteristics, including low stability, short half-life, and a lack of oral bioavailability.